A gut meta-interactome map reveals modulation of human immunity by microbiome effectors


  • Young Veronika
  • Dohai Bushra
  • Hitch Thomas
  • Hyden Patrick
  • Weller Benjamin
  • van Heusden Niels
  • Saha Deeya
  • Macgregor Jaime Fernandez
  • Maseko Sibusiso
  • Lin Chung-Wen
  • Boujeant Mégane
  • Choteau Sébastien
  • Ober Franziska
  • Schwehn Patrick
  • Rothballer Simin
  • Altmann Melina
  • Altmann Stefan
  • Strobel Alexandra
  • Rothballer Michael
  • Tofaute Marie
  • Heinig Matthias
  • Clavel Thomas
  • Twizere Jean-Claude
  • Vincentelli Renaud
  • Boes Marianne
  • Krappmann Daniel
  • Falter Claudia
  • Rattei Thomas
  • Brun Christine
  • Zanzoni Andreas
  • Falter-Braun Pascal

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SUMMARY The molecular mechanisms by which the gut microbiome influences human health remain largely unknown. Pseudomonadota is the third most abundant phylum in normal gut microbiomes. Several pathogens in this phylum can inject so-called virulence effector proteins into host cells. We report the identification of intact type 3 secretion systems (T3SS) in 5 - 20% of commensal Pseudomonadota in normal human gut microbiomes. To understand their functions, we experimentally generated a high-quality protein-protein meta-interactome map consisting of 1,263 interactions between 289 bacterial effectors and 430 human proteins. Effector targets are enriched for metabolic and immune functions and for genetic variation of microbiome-influenced traits including autoimmune diseases. We demonstrate that effectors modulate NF-κB signaling, cytokine secretion, and adhesion molecule expression. Finally, effectors are enriched in metagenomes of Crohn’s disease, but not ulcerative colitis patients pointing toward complex contributions to the etiology of inflammatory bowel diseases. Our results suggest that effector-host protein interactions are an important regulatory layer by which the microbiome impacts human health.

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